We have demonstrated that administration of DTP vaccine to mice causes alterations in hepatic drug metabolism in a dose and time dependent manner. The mechanism for the observed changes is unknown, as are the components responsible for the alterations. Endotoxin (LPS) is a common component of many bacterial vaccines and causes a variety of effects in vivo. In order to understand the role of LPS in vaccine-induced hepatotoxicity, endotoxin sensitive and endotoxin resistant mice have been treated with vaccines and endotoxin. There is a marked difference in hexobarbital-induced sleep times and cytochrome P-450 levels between LPS-sensitive and LPS-resistant mice treated with 50 ug of B.pertussis LPS. In contrast, DTP vaccine pretreatment causes similar responses in both strains of mice. These differences between LPS and DTP vaccine persist for at least 1 week. Polymyxin B sulfate is able to completely neutralize the effects of soluble LPS, but there is still residual rabbit and limulus endotoxic activity when it is mixed with DTP vaccine. This may be due to incomplete accessibilty of the endotoxin in the vaccine. An additional approach has been to use DT vaccine mixed with LPS to simulate bound endotoxin. This mixture does not alter drug metabolism in the same manner as DTP vaccine. The acellular version of DTP does not produce the same effects as the whole cell vaccine in mice. Serum cytokine levels (IL6 and TNF) are elevated in a number of disease states or following injury or trauma. We have found that IL6 and TNF are elevated 2-4 hours after a single dose of vaccine or endotoxin. The serum profiles of these cytokines are similar in responsive mice treated with either LPS or DTP vaccine; in nonresponsive mice neither agent produces a marked increase. Studies are continuing to identify other factors which may be involved.